Members of the group of naturally-occurring compounds known collectively as phytoestrogenic isoflavonoids have recently been shown to have significant effects on human health, including antioxidant behavior (Jha et al. 1985), antitiumor activity (Hirano et al. 1989; Hirano et al., 1994), and anti-mutagenic activity (Hartman and Shankel, 1990). Furthermore it has been shown that one member of this compound group, the isoflavonoid compound daidzein, acts synergistically with the anticancer drug tamoxifen in prevention of mammary tumors (Constantinou et al. 2005). It has also been demonstrated that intestinal bacteria present in many, but not all, mammals and humans metabolize daidzein through transformation to the reduction product S-(−)-equol [7-hydroxy-3-(4′-hydroxypphenyl)-chroman] (Wang et al. 2005). Equol is a nonsteroidal estrogen of the isoflavone class. It is thought that daidzein serves merely as a precursor or prodrug to equol, and that equol may be a more generally effective anticancer compound than is daidzein. There is therefore a need for a method of obtaining equol in sufficient quantities for both research and medicinal purposes.
Equol contains a single enantiomeric carbon atom and exists in both R- and S-isomers and as the racemic modification, (+/−)-equol. Methyala et al. (2004) demonstrated that (+/−)-equol can be separated into its two optically pure components through chromatography on an appropriate chiral support. This process is not easily performed, however.
The synthesis of (+/−)-equol was first reported by Wessely and Prillinger in 1939. These workers reduced the readily-available daidzein to racemic equol using a very large amount of a specially-prepared palladium catalyst under conditions of high-pressure hydrogenation. Lamberton et al. reported in 1978 that the catalyst preparation of Wessely and Prillinger was impractical and that the catalyst could not be reused; furthermore, commercial grades of palladium catalysts were ineffective in carrying out this conversion. Lamberton et al. (1978) described the reduction of daidzein diacetate to equol diacetate in good yield using the specially prepared catalyst of Wessely and Prillinger, but in addition to the difficulty of obtaining this catalyst, they discovered that the reaction required 30 g of the catalyst to produce 4.1 g of product. Furthermore, an additional step, saponifying the acetate groups of equol diacetate, was necessary to obtain equol.
Wahala and Hase (1989) attempted to reduce daidzein under the condition of palladium-catalyzed hydrogen-transfer reduction rather than pressure hydrogenation. Using ammonium formate as the hydrogen donor and ordinary commercially available palladium/charcoal catalyst, they obtained only partially reduced isoflavanones and isoflavanols, and no equol. However in 2004 Muthyala et al. reported that hydrogen-transfer reduction using ammonium formate in acetic acid and palladium hydroxide on carbon catalyst (“Pearlman's catalyst”) converted daidzein into equol in 61% yield. In order to obtain equol in this yield it was necessary to chromatograph the initially-obtained brown oily crude product to remove nearly 40% of undesirable impurities.
Using methods existing in the art, equol is generally considered to be a relatively expensive compound (e.g., $275 per 5 mg sample). Because it may be effective for a variety of therapeutic applications such as cancer therapy, treatment of benign prostate hyperplasia, and hormone-mediated conditions such as bone loss, hair loss, and abnormal hair growth, for example, a need exists for methods of synthesizing biologically active equol to produce an affordable product for therapeutic use.